RESUMEN
CRISPR-Cas9 has been used successfully to introduce indels in somatic cells of rodents; however, precise editing of single nucleotides has been hampered by limitations of flexibility and efficiency. Here, we report technological modifications to the CRISPR-Cas9 vector system that now allows homology-directed repair-mediated precise editing of any proto-oncogene in murine somatic tissues to generate tumor models with high flexibility and efficiency. Somatic editing of either Kras or Pik3ca in both normal and hyperplastic mammary glands led to swift tumorigenesis. The resulting tumors shared some histological, transcriptome, and proteome features with tumors induced by lentivirus-mediated expression of the respective oncogenes, but they also exhibited some distinct characteristics, particularly showing less intertumor variation, thus potentially offering more consistent models for cancer studies and therapeutic development. Therefore, this technological advance fills a critical gap between the power of CRISPR technology and high-fidelity mouse models for studying human tumor evolution and preclinical drug testing.
Asunto(s)
Edición Génica , Neoplasias , Animales , Ratones , Humanos , Edición Génica/métodos , Sistemas CRISPR-Cas/genética , Neoplasias/genética , Neoplasias/terapia , Reparación del ADN por Recombinación , Modelos Animales de EnfermedadRESUMEN
The neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD) both have a myriad of risk factors including genetics, environmental exposures, and lifestyle. However, aging is the strongest risk factor for both diseases. Aging also profoundly influences the immune system, with immunosenescence perhaps the most prominent outcome. Through genetics, mouse models, and pathology, there is a growing appreciation of the role the immune system plays in neurodegenerative diseases. In this review, we explore the intersection of aging and the immune system in AD and PD.